In patients with multiple myeloma, completion of mRNA-based vaccination schemes failed to yield detectable SARS-CoV-2 Omicron-neutralizing antibodies and S1-RBD–specific CD8+ T cells in approximately 60% and 80% of the cases, respectively. Patients who develop breakthrough infections exhibited very low levels of live-virus neutralizing antibodies and the absence of follicular T helper cells.
The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was classified by the World Health Organization on November 26, 2021, as a novel variant of concern (VOC; ref. 1). Notably, the Omicron (B.1.1.529) evolved into five sublineages, numbered BA.1 to BA.5. Omicron is characterized by its contagiousness and by vaccine-escape mutations. The receptor-binding domain of the S protein (S1-RBD), which binds to the host receptor ACE2, is essential for SARS-CoV-2 infectivity. S1-RBD mutations mediate escape from vaccine-induced neutralizing antibodies (nAb). BA.1 and BA.2 share 12 mutations in S1-RBD (1). BA.4 and BA.5 (referred to below as BA.4/5), presumably originated from BA.2, and contain additional mutations in the RBD (2). These mutations likely contribute to immune evasion as individuals previously infected with earlier SARS-CoV-2 variants can be reinfected with Omicron (1), and sera of vaccinees with BA.1 breakthrough infections (BTI) show reduced neutralization of BA.4/5 (2). As compared with previous VOC, Omicron appears less pathogenic based on rates of hospitalizations and deaths (1). However, Omicron pathogenicity is likely underestimated because of the herd immunity induced by prior infections and vaccinations in the general population and may be more severe in immunocompromised individuals.
In triple-vaccinated healthcare workers, subsequent infection with Omicron boosted nAb, memory B- and T-cell responses against Wuhan, Alpha, and Delta but not Omicron itself (3). Half of the subjects failed to develop T-cell response to Omicron S1 antigen, and all showed reduced responses to the Omicron peptide pool, irrespective of the SARS-CoV-2 infection history. Furthermore, infection with Alpha resulted in reduced potency of nAbs. Surprisingly, Omicron infection following prior Wuhan strain infection did not enhance crossreactive antibody binding, T-cell recognition, memory B-cell frequency, or nAb potency (3).
Tailoring vaccine boosters to new variants could potentially improve protection. In a randomized trial, boosting with heterologous Beta-vaccine MVB.1.351 (an adjuvanted recombinant spike protein derived from the Beta variant) after two doses of mRNA-based BNT162b2 vaccine (encoding Wuhan strain-derived spike antigen) resulted in much higher nAb titers against Beta, Wuhan, Delta, and Omicron BA.1 variants than did boosting with vaccines with the original strain specificities, either mRNA-based (BNT162b2) or recombinant-protein (MVD614) in 223 participants (4). The Beta vaccine boost also induced high levels of specific polyfunctional CD4+ Th1 responses (4).
Apparently, the quality of the T-cell response also determines effective protection against the virus. Early appearance of T cells reactive to peptide pools of the ancestral SARS-CoV2 strain correlates with a shorter duration of infection (5). Fahrner and colleagues reported a correlation between preexisting (before 2020) SARS-CoV-2–specific T-cell immune responses with a type 2 helper or cytotoxic (Th2/Tc2) cytokine profile and susceptibility to infection with SARS-CoV-2 or reinfection by VOC (5). Moreover, although the breadth of the peptide recognition profile across the ORFeome did not correlate with infections during the first wave of the pandemic, a type 1 helper or cytotoxic (Th1/Tc1) response selective for the S1-RBD region appeared to be essential for protection against BTI (5).
The findings above were established in the healthy general population. In the context of cancer, immune responses to a vaccine become dramatically more complex due to the impact of cancer itself, anticancer therapies, and associated morbidities. In patients with hematologic neoplasia, humoral response to mRNA were inferior to rates achieved in patients harboring solid tumors and in healthy donors (HD; refs. 6, 7). Moreover, patients with active disease showed lower antibody titers compared with those in remission. To a significant extent, this effect can be attributed to B cell–targeting anticancer therapies. Among blood cancer types, the lowest seroconversion was seen in patients with chronic lymphocytic leukemia (CLL) and other B-cell malignancies (6). For example, in a cohort of 77 German multiple myeloma (MM) patients (vs. 24 controls), only 44% were serological responders to the Alpha variant (7). Antibody titers improved with a third dose, but neutralization capacity against Omicron remained poor in both MM and HD.
Mortality rate following SARS-CoV-2 infection is particularly high among patients with hematologic malignancies. Before vaccination became available, a study of 41 blood cancer patients with COVID-19 correlated lower CD8+ T-cell counts with higher mortality (8). In the German study (7), only one third of MM patients mounted robust T-cell responses after two mRNA vaccine doses. The compensatory role of T cells is likely important in the context of B-cell dysfunction, but little is known about quality and magnitude of CD8+ T-cell responses elicited by mRNA vaccines in myeloma patients, and whether and how they contribute to protection from BTI with the current VOC.
In the previous issue of Blood Cancer Discovery, Azeem and colleagues offer first answers to these questions in their comprehensive analysis of cross-protection against Omicron (including BA.1, BA.2, and BA.5) after two or three administrations of currently FDA-approved mRNA vaccines (based on the Wuhan strain) using serological and functional assays and high dimensional immunophenotyping in a cohort enrolling 331 patients with MM (Fig. 1; ref. 9).
Although MM patients could develop S1-RBD–specific antibodies following mRNA vaccination, suboptimal induction of nAbs were detected following the first two doses of mRNA vaccines in this patient population (6). Completing the immunization process with a third boost increased nAbs in 82% but only 33% to 44% patients against Wuhan-Hu-1 and Omicron variants, respectively (9). nAb titers against BA.5 were 14-fold lower than against the ancestral strain, even following booster vaccination (9). nAb responses were lower in males and in patients with hypogammaglobulinemia (9). Seronegativity was associated with a lower proportion of B cells and naïve T cells, as well as a higher percentage of CD27− T cells. The abundance of circulating CD16+CD11c+CD14−DR+ myeloid and dendritic cells correlated with higher seropositivity as well as T-cell responses (9). The booster vaccine overcame the adverse effect of prior anti-CD38 antibody (but not BCMA-directed) therapy on nAbs titers observed following the first two doses. Patients on lenalidomide treatment had higher nAbs than patients on other therapies. Booster dose also led to increase in S1-RBD–specific class-switched memory IgM−CD27+ B cells, whereas B cells elicited with earlier doses exhibited more transitional memory phenotypes (9). RBD-specific B cells in MM patients also often presented a T-bet+CD11c+ phenotype, which is implicated in aging and extrafollicular responses. Black patients, who exhibit an increased risk of developing MM, mounted higher levels of nAbs after the second vaccination as compared with non-Blacks, but these differences did not persist after another boost. Of note, RBD-specific B cells contained a higher proportion of T-bet+ cells in Black patients (9).
In this MM cohort, vaccine-induced T-cell responses were measured with 3 complementary methods (interferon-γ ELISPOT, activation-induced marker assay, and TCR sequencing). Vaccine-induced spike-specific T cells were detected in patients without seroconversion and cross-recognized VOC-specific peptides, but were predominantly effector CD4+ T cells with a selective increase in TCRs against surface glycoproteins (compared with other viral proteins; ref. 9). Importantly, in contrast to HD, MM patients failed to mount spike-specific CD8+ T-cell response even after the third vaccination.
Finally, those MM patients who were diagnosed with Omicron BTI following booster vaccinations had relatively low titers of nAbs capable of neutralizing the tested BA variants, correlating with reduced follicular T helper cell responses (Fig. 1; ref. 9).
During the pandemic waves, immune responses to experimental and FDA-approved vaccines have been monitored to evaluate their efficacy and to determine the optimal timing of repeated immunizations. For this purpose, titers of antibodies specific to trimeric S protein or RBD served as a good proxy of protective immunity in the general population (2). However, when it comes to patients with MM, antibody titers do not correlate with symptomatic BTI, whereas live-virus neutralization does (9). As antibody titers overestimate the magnitude of neutralizing humoral response, functional readouts appear more accurate in estimating protective immunity in immunocompromised populations.
Another study recently published in Cancer Research Communications enrolled 67 non-Hodgkin lymphoma (NHL) or CLL patients to monitor IgG, IgA, and IgM responses against VOC, including Omicron BA.5 after booster vaccination. As compared with HD, patients had a much lower fold increase and total anti-S1 RBD-binding titers after booster. Binding titers against BA.1 were reduced by a median of 4.8-fold compared with the ancestral strain in both patients with NHL/CLL and HD. Titers against BA.1, BA.2, and BA.3 strains were largely equivalent. Here again, nAb titers negatively correlated with recent anti-CD20 therapy and low B-cell numbers. Importantly, all 43% patients who showed anti-Omicron BA.1 nAb after booster also reacted with BA.5 (Fig. 1) (10).
These findings highlight that the TFH and consequently the TFH/B-cell cross-talk, which is required for the generation of high-affinity neutralizing antibodies and appears defective in immunocompromised patients (with HM, hypogammaglobulinemia or monoclonal gammapathy of unknown significance), might be compensated by the elicitation of S1-RBD–specific Tc1 responses. Thus, the development of the current bivalent or Omicron variant-adapted vaccines to be administered during the remission phase or treatment-free intervals may compensate for some of these limitations (3). Future strategies applicable to HM patients might also include the development of broadly neutralizing antibodies for passive immunization or that of vaccines specifically designed to induce Omicron-specific CD8+ T-cell responses with a Tc1 polarity (Fig. 1).
L. Zitvogel reports personal fees from Everimmune and HOOKIPA, grants from 9 meters, Pileje, and Daichi Sankyo outside the submitted work; in addition, L. Zitvogel has a patent for EP21171380.5 pending. G. Kroemer reports grants from Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Tollys, and Vascage, and personal fees from Reithera outside the submitted work; in addition, G. Kroemer has a patent for WO2014020041-A1 issued to Bayer, a patent for WO2014020043-A1 issued to Bayer, a patent for WO2008057863-A1 issued to Bristol Myers Squibb, a patent for WO2019057742A1 pending to Osasuna Therapeutics, a patent for WO2022049270A1 pending to Pharmamar, a patent for WO2022048775-A1 pending to Pharmamar, and a patent for EP3684471A1 pending to Therafast Bio. G. Kroemer is on the Board of Directors of the Bristol Myers Squibb Foundation France, and is a scientific cofounder of everImmune, Osasuna Therapeutics, Samsara Therapeutics, and Therafast Bio. No disclosures were reported by the other authors.
L. Zitvogel has been supported by Gustave Roussy Philanthropia, Malakoff Humanis, ARC, and by the French Ministery of Health. L. Derosa has been supported by Gustave Roussy Philanthropia.